Zolbetuximab, the first monoclonal antibody targeting claudin 18.2 (CLDN18.2), is approved as first-line treatment for patients with HER2-negative and CLDN18.2-positive gastric or gastroesophageal junction cancers, offering new hope to patients who previously derived limited benefit from molecular targeted therapies or immune checkpoint inhibitors...Next-generation modalities such as ADCs, bispecific antibodies, and CAR-T cell therapies have shown efficacy even in patients with lower CLDN18.2 expression, suggesting potential to expand treatment eligibility. Moving forward, deeper understanding of gastrointestinal toxicities associated with CLDN-targeted therapies, elucidation of resistance mechanisms, and development of rational combination strategies will be essential to maximize therapeutic benefit in patients with CLDN18.2-positive gastric cancer.

IBI389 showed manageable safety profiles in patients with advanced solid tumors and preliminary efficacy in Claudin18.2-positive patients with GC/GEJC.

Zolbetuximab exemplifies a novel therapeutic class which can be classified as targeted cytolytic antibodies. Future work should test combinations with checkpoint blockade, refine biomarkers and define resistance mechanisms.

SPOTLIGHT and GLOW trials evaluated the anti-CLDN18.2 monoclonal antibody (mAb) zolbetuximab in combination with first-line chemotherapy, and established CLDN18.2 as a therapeutic target, initiating a paradigm shift toward a biomarker-driven treatment approach in AGC...Therefore, as research progresses, CLDN18.2-targeted therapy is poised to become a cornerstone of treatment across multiple disease stages and cancer types. This review describes the biological role of CLDN18.2 in normal gastric epithelium and gastric carcinogenesis and summarizes the current therapeutic landscape and future perspectives targeting CLDN18.2 in AGC.

These measures reflect reporting disproportionality within a spontaneous-reporting system and should not be interpreted as incidence or causality. These exploratory findings support proactive, guideline-based antiemetic strategies-particularly for younger female patients-and warrant prospective confirmation.

The CR101 antibody exhibits high affinity and specificity for claudin18.2, demonstrating superior tumor cell-killing efficiency compared to IMAB362...Transcriptomic analysis revealed that CR101-ADC primarily affects cytoskeletal, inflammatory, and stress pathways and represents a promising candidate for the treatment of gastrointestinal malignancies. Collectively, these findings demonstrate that CR101-ADC combines high specificity, potent intracellular drug delivery, and favorable safety, representing a promising next-generation therapeutic candidate for CLDN18.2-positive gastrointestinal cancers.

P2, N=100, Recruiting, Universitaire Ziekenhuizen KU Leuven | Not yet recruiting --> Recruiting | Trial primary completion date: Oct 2029 --> Dec 2029

P1/2, N=320, Recruiting, Suzhou Transcenta Therapeutics Co., Ltd. | Trial completion date: May 2025 --> Dec 2026 | Trial primary completion date: Feb 2025 --> Jun 2026

Zolbetuximab plus chemotherapy was administered to real-world patients with CLDN18.2-positive AGC with acceptable safety profiles and showed preliminary antitumor efficacy. Nevertheless, some adverse events warrant careful monitoring.

P1/2, N=150, Active, not recruiting, Suzhou Transcenta Therapeutics Co., Ltd. | Trial completion date: Sep 2025 --> Nov 2026 | Trial primary completion date: May 2025 --> May 2026

P3, N=820, Not yet recruiting, Suzhou Transcenta Therapeutics Co., Ltd. | Trial completion date: Jan 2026 --> Jan 2030 | Trial primary completion date: Oct 2025 --> Oct 2029

These observations suggest that gastric wall changes detectable using US are closely linked to nausea and may reflect underlying gastric injury. This report also highlights the potential of bedside US monitoring to help predict and prevent nausea during zolbetuximab therapy.